Paclitaxel BC Cancer Drug Manual © All rights reserved. Page 1 of 11 Paclitaxel This document may not be reproduced in any form without the express written permission of BC Cancer Provincial Pharmacy. Developed: 1 June 2012 Revised: 30 December 2019 DRUG NAME: Paclitaxel SYNONYM(S): benzenepropanoic acid 1 COMMON TRADE NAME(S): TAXOL®, ONXOL® CLASSIFICATION: antimicrotubule agent Special pediatric considerations are noted when applicable, otherwise adult provisions apply. MECHANISM OF ACTION: Paclitaxel is a taxane. Paclitaxel binds to tubulin, the protein component of microtubules, simultaneously promoting their assembly and disassembly to form stable, nonfunctional microtubules. 1,2 Although some reports indicate a cross-reactivity rate of 90% between docetaxel and paclitaxel, others suggest it does not occur consistently. 2,3 Stabilization of microtubules blocks cells in the M phase of the cell cycle, inhibiting cell division and causing cell death. 2 Paclitaxel acts as a radiosensitizing agent by blocking cells in the G2 phase. 4 Paclitaxel is an immunosuppressant. 5,6 PHARMACOKINETICS: Oral Absorption no information found Distribution biphasic: initial distribution to peripheral compartment, then slow efflux from the peripheral compartment; widely distributed into body fluids and tissues 1,7 ; small changes in dose may lead to large changes in peak plasma concentrations and total drug exposure due to saturable, nonlinear pharmacokinetics 2 cross blood brain barrier? 2,8 no volume of distribution 1,2,5,6 67 L/m² for 1-6 h infusion; varies with dose and infusion time; 198-688 L/m² for 24 h infusion plasma protein binding 1,2,5 88-98% Metabolism extensively metabolized in liver via CYP 2C8 (primarily) and CYP 3A4; activity of metabolites is unknown 1,2,7 metabolite(s) 2,4,9 • 67% as 6α-hydroxypaclitaxel via CYP 2C8; • 37% as 3-p-hydroxypaclitaxel and 6α,3-p- dihydroxypaclitaxel via CYP 3A4 Excretion primarily via bile 1,2,5,7,8 urine 14% (1-13% as unchanged drug) feces 71% (5% as unchanged drug) terminal half life 1,2,6,7 10 h; varies with dose and infusion time clearance 1,2,7 12 L/h/m²; varies with dose and infusion time Children 2 clearance: 19 to 260 L/m² Adapted from standard reference 7 unless specified otherwise.
DRUG NAME: Paclitaxel
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-Paclitaxel
BC Cancer Drug Manual© All rights reserved. Page 1 of 11 Paclitaxel This document may not be reproduced in any form without the express written permission of BC Cancer Provincial Pharmacy. Developed: 1 June 2012 Revised: 30 December 2019
DRUG NAME: Paclitaxel SYNONYM(S): benzenepropanoic acid1 COMMON TRADE NAME(S): TAXOL®, ONXOL® CLASSIFICATION: antimicrotubule agent
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
MECHANISM OF ACTION: Paclitaxel is a taxane. Paclitaxel binds to tubulin, the protein component of microtubules, simultaneously promoting their assembly and disassembly to form stable, nonfunctional microtubules.1,2 Although some reports indicate a cross-reactivity rate of 90% between docetaxel and paclitaxel, others suggest it does not occur consistently.2,3 Stabilization of microtubules blocks cells in the M phase of the cell cycle, inhibiting cell division and causing cell death.2 Paclitaxel acts as a radiosensitizing agent by blocking cells in the G2phase.4 Paclitaxel is an immunosuppressant.5,6
PHARMACOKINETICS: Oral Absorption no information found Distribution biphasic: initial distribution to peripheral compartment, then slow efflux from the peripheral
compartment; widely distributed into body fluids and tissues1,7; small changes in dose may lead to large changes in peak plasma concentrations and total drug exposure due to saturable, nonlinear pharmacokinetics2 cross blood brain barrier?2,8 no volume of distribution1,2,5,6 67 L/m² for 1-6 h infusion; varies with dose and infusion
time; 198-688 L/m² for 24 h infusion plasma protein binding1,2,5 88-98%
Metabolism extensively metabolized in liver via CYP 2C8 (primarily) and CYP 3A4; activity of metabolites is unknown1,2,7 metabolite(s)2,4,9 • 67% as 6α-hydroxypaclitaxel via CYP 2C8;
• 37% as 3-p-hydroxypaclitaxel and 6α,3-p- dihydroxypaclitaxel via CYP 3A4
Excretion primarily via bile1,2,5,7,8 urine 14% (1-13% as unchanged drug) feces 71% (5% as unchanged drug) terminal half life1,2,6,7 10 h; varies with dose and infusion time clearance1,2,7 12 L/h/m²; varies with dose and infusion time
Children2 clearance: 19 to 260 L/m²
Adapted from standard reference7 unless specified otherwise.
Paclitaxel
BC Cancer Drug Manual© All rights reserved. Page 2 of 11 Paclitaxel This document may not be reproduced in any form without the express written permission of BC Cancer Provincial Pharmacy. Developed: 1 June 2012 Revised: 30 December 2019
USES: Primary uses: Other uses: *Breast cancer Lung cancer, small cell2 *Lung cancer, non-small cell Esophageal cancer2 *Ovarian cancer Bladder cancer2 *Kaposi’s Sarcoma Head and Neck cancer2 Cervical cancer2 Endometrial cancer2
*Health Canada approved indication
SPECIAL PRECAUTIONS: Caution: • preexisting liver impairment may impair elimination of paclitaxel1,7; dose reduction is suggested2,9 Special populations: • elderly patients may have more myelosuppression, neuropathy and cardiovascular toxicities2 • patients with AIDS-related Kaposi’s sarcoma may have more hematologic toxicities, infections and febrile
neutropenia.7 Carcinogenicity: no information found Mutagenicity: Not mutagenic in Ames test and mammalian in vitro mutation test. Paclitaxel is clastogenic in human lymphocytes in vitro but not in other mammalian in vivo chromosome tests.1,2,7 Fertility: In animal studies, reduced fertility has been observed, with decreased pregnancy rates and increased embryo loss in females and testicular atrophy/degeneration in males.1,2 Pregnancy: FDA Pregnancy Category D.5,10 There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). Paclitaxel has shown to be embryotoxic and fetotoxic in animal studies; soft tissue and skeletal malformations have been reported.1,2,7 Breastfeeding is not recommended due to the potential secretion into breast milk.1,2,7
SIDE EFFECTS: The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials.11-14
ORGAN SITE SIDE EFFECT
blood and lymphatic system/ febrile neutropenia
anemia (62-78%, severe 6-16%)1,7
febrile neutropenia (2%)6
leukopenia (86-90%, severe 4-17%)1,7
neutropenia (87-90%, severe 27-52%)1,2,7; nadir 10-12 days, recovery 15-21 days; may require dose reduction
Paclitaxel
BC Cancer Drug Manual© All rights reserved. Page 3 of 11 Paclitaxel This document may not be reproduced in any form without the express written permission of BC Cancer Provincial Pharmacy. Developed: 1 June 2012 Revised: 30 December 2019
ORGAN SITE SIDE EFFECT
Clinically important side effects are in bold, italics
thrombocytopenia (6-20%, severe 1-7%)1,2,7; nadir 8-9 days2
cardiac bradycardia (3-4%); first 3 h of infusion1,7; see paragraph following Side Effects table
cardiovascular events (severe 1-2%)1,7; see paragraph following Side Effects table
ear and labyrinth hearing loss, tinnitus, vertigo, ototoxicity (<1%)
eye optic nerve and/or visual disturbances, photopsia, visual floaters (<1%); generally reversible, may be dose-related
gastrointestinal emetogenic potential: low-moderate15
anorexia (25%)1
constipation (18%)1
nausea and vomiting (44-52%)
general disorders and administration site conditions
extravasation hazard: irritant,16,17 treat as vesicant18; see paragraph following Side Effects table edema (17-21%, severe 1%); localized under skin at no specific site
fever (12%)7
immune system hypersensitivity reactions (5-42%, severe 1-2%)1,7,19; see paragraph following Side Effects table
infections and infestations
infections (18-30%, severe 1%); primarily urinary tract and upper respiratory tract1,7
injury, poisoning, and procedural complications
radiation recall dermatitis2
investigations ECG abnormalities (8-14%, severe <1%)1,2,7; see paragraph following Side Effects table alkaline phosphatase, elevated (18-22%, severe 1%)1,7
AST, elevated (18-19%, severe 1%)1,7
bilirubin, elevated (4-7%, severe 1%)1,7
musculoskeletal and connective tissue
motor neuropathy, with resultant minor distal weakness (<1%)
peripheral neuropathy (52-64% severe 2-4%)1,7; see paragraph following Side Effects table
respiratory, thoracic and mediastinal
Paclitaxel
BC Cancer Drug Manual© All rights reserved. Page 4 of 11 Paclitaxel This document may not be reproduced in any form without the express written permission of BC Cancer Provincial Pharmacy. Developed: 1 June 2012 Revised: 30 December 2019
ORGAN SITE SIDE EFFECT
skin and subcutaneous tissue
alopecia (87-93%)1,7; usually complete, generally occurs 14-21 days after administration of paclitaxel; onset sudden, often occurring in a single day2 nail discolouration (2%)7
rash (12-14%)1,7
phlebitis1,7
Adapted from standard reference7 unless specified otherwise.
Arthralgia/myalgia may be severe in some patients; however, there is no consistent correlation between cumulative dose and infusion duration of paclitaxel and frequency or severity of the arthralgia/myalgia. Symptoms are usually transient, occurring within 2 or 3 days after paclitaxel administration, and resolving within days.2,7 If arthralgia/myalgia is not relieved by adequate doses of ibuprofen, or short-term, low-dose dexamethasone or prednisone20,21, gabapentin may be tried.20-22 Dose reducing paclitaxel may lessen the severity of arthralgias/myalgias; however, there is no data on efficacy of reduced doses in a curative setting. Dose reduction should be considered only if symptom severity precludes continuing paclitaxel.11,12,23 Cardiovascular effects present as bradycardia, hypotension and ECG changes. Bradycardia and hypotension typically occur during the first 3 hours of infusion; however, they are usually asymptomatic and do not require treatment. Paclitaxel administration may require interruption or discontinuation in some cases. Frequency of hypotension and bradycardia is not influenced by dose, schedule or prior anthracycline therapy. Common ECG changes are non-specific repolarization abnormalities, sinus bradycardia, sinus tachycardia, and premature beats. Among patients with normal ECG at baseline, prior therapy with anthracyclines did not influence the frequency of ECG abnormalities. Severe cardiovascular effects are rarely reported, including cases of atrial fibrillation, supraventricular tachycardia, myocardial infarction, congestive heart failure, and thromboembolic events. When reported, these patients had underlying disease or previous radiotherapy or chemotherapy which was thought to have contributed to the event.2,7 Paclitaxel extravasation may rarely cause local tissue necrosis, leading to the suggestion that paclitaxel may have vesicant properties. In some reports, patients have experienced recall reactions from previous paclitaxel extravasations. No correlation has been made between concentration or volume of paclitaxel extravasated and the risk of tissue necrosis. Extravasation injuries due to paclitaxel may be either immediate or delayed and thus patients may require an extended follow-up; patient complaints of pain, burning, or stinging at the injection site occurring several days after the infusion should be investigated. Specific treatment recommendations for paclitaxel extravasation are still unclear as experience is anecdotal.7,16,17 For management of extravasation reactions, see BC Cancer Policy Number III-20 Prevention and Management of Extravasation of Chemotherapy. Hypersensitivity reactions typically occur within the first 10 minutes of the first two cycles.2,24 Reactions are caused by either a histamine release in response to polyoxyl 35 castor oil (Cremophor® EL), or a non-IgE mediated reaction to the taxane moiety. Frequent, minor hypersensitivity reactions include: flushing (28%), rash (12%), hypotension (4%), dyspnea (2%), tachycardia (2%), and hypertension (1%). Chills, abdominal pain, and back pain are more rare.2,7 Severe hypersensitivity reactions include: dyspnea requiring bronchodilators, hypotension requiring treatment, flushing, chest pain, tachycardia, angioedema, and generalized urticaria. Severe reactions rarely occur after the third cycle of treatment.2,7 The incidence and severity of hypersensitivity reactions are reduced with premedication although rare, fatal reactions may occur despite premedication.7. A single IV dexamethasone dose with an antihistamine and an H2-antagonist reduces the incidence of hypersensitivity reactions from 40% to 2-3%.7,25 The frequency and severity of hypersensitivity reactions are not affected by the dose or duration of infusion of paclitaxel.7,26 For management of hypersensitivity reactions, see BC Cancer Protocol SCDRUGRX Management of Hypersensitivity Reactions to Chemotherapeutic Agents.
Rechallenge after a severe hypersensitivity reaction: The occurrence of hypersensitivity reactions does not preclude rechallenge with paclitaxel. In the event of a hypersensitivity reaction, the patient may be rechallenged the same day after additional premedication, slowing the rate of infusion, and close monitoring.23,25 Subsequent cycles may benefit from a regimen of oral dexamethasone given 12 and 6 hours before paclitaxel, plus antihistamines and H2-antagonists given 30 minutes to 1 hour before paclitaxel.24,26,27 Consider substituting paclitaxel with docetaxel or implementing a desensitization protocol if a patient develops a reaction following a rechallenge.24 For management of hypersensitivity reactions, see BC Cancer Protocol SCDRUGRX Management of Hypersensitivity Reactions to Chemotherapeutic Agents. Peripheral sensory neuropathy presents with numbness and tingling in a stocking-and-glove distribution, perioral numbness, and hyperesthesia. Onset of symptoms can be within days following infusion. Frequency of symptoms increases with repeated exposure and cumulative dose.2,7 Pre-existing neuropathies from prior therapies are not a contraindication for treatment with paclitaxel; however, the incidence of neuropathy appears to be increased in this patient population. A dose reduction of 20% is recommended for all subsequent cycles of paclitaxel for patients who experience severe peripheral neuropathy. Sensory neuropathy usually improves or resolves within months of paclitaxel discontinuation.7
INTERACTIONS:
paclitaxel clearance is decreased by 25-33% when given after cisplatin
preferred method is to give paclitaxel first when administering as sequential infusions
dexamethasone1,7 does not affect protein binding of paclitaxel
diphenhydramine1 does not affect protein binding of paclitaxel
disulfiram29 development of acute alcohol intolerance reactions
inhibition of aldehyde dehydrogenase by disulfiram, leading to development of toxic metabolites of ethanol (found in the solution)
avoid disulfiram concurrently with paclitaxel administration
doxorubicin2,7,28 may increase cardiac toxicity from doxorubicin when given concurrently with paclitaxel
doxorubicin clearance is decreased leading to increased plasma levels of doxorubicin and doxorubicinol
monitor for increased cardiotoxicity
metronidazole and derivatives29
development of acute alcohol intolerance reactions; the risk for most patients appears slight
inhibition of aldehyde dehydrogenase by metronidazole, leading to development of toxic metabolites of ethanol (found in solution)
avoid metronidazole and its derivatives concurrently with paclitaxel administration
vaccines, live29 enhanced viral replication may increase the risk of disseminated disease
decreased immune response allows live vaccine to produce infection
avoid live vaccines during treatment
BC Cancer Drug Manual© All rights reserved. Page 6 of 11 Paclitaxel This document may not be reproduced in any form without the express written permission of BC Cancer Provincial Pharmacy. Developed: 1 June 2012 Revised: 30 December 2019
AGENT EFFECT MECHANISM MANAGEMENT
warfarin29 may increase anticoagulant effect of warfarin when given concurrently with paclitaxel
paclitaxel may displace warfarin from plasma protein binding sites when given concurrently
monitor INR and adjust warfarin dosing accordingly; consider use of LMWH with chemotherapy30
Paclitaxel is a substrate of CYP 3A4 and CYP 2C8 isoenzymes. Strong inhibitors of CYP 3A4 or 2C8 may decrease paclitaxel metabolism resulting in increased plasma levels and toxicity. Avoid concurrent use if possible; if unavoidable, consider reducing the paclitaxel dose.2,7,28 Strong inducers of CYP 3A4 or 2C8 may increase paclitaxel metabolism, potentially resulting in a reduced therapeutic effect of paclitaxel.1,2,7
SUPPLY AND STORAGE: Injection: Accord Healthcare Inc. supplies paclitaxel as 30 mg, 100 mg, and 300 mg vials in a concentration of 6 mg/mL. Store at room temperature. Product may precipitate if refrigerated; precipitate redissolves at room temperature. Non- medicinal ingredients per mL of solution: 527 mg Cremophor® EL (polyethoxylated castor oil) and 39.1%(w/v) ethanol.31 Biolyse Pharma supplies paclitaxel as 30 mg and 100 mg single dose vials and a 300 mg multi-dose vial in a concentration of 6 mg/mL. Refrigerate. Do not freeze. Potency is not affected when transported or stored for up to 2 months at room temperature. Non-medicinal ingredients per mL of solution: 527 mg Cremophor® EL (polyethoxylated castor oil) and 49.7%(v/v) alcohol.1 Pfizer Canada Inc. (Hospira Healthcare) supplies paclitaxel as 30 mg, 100 mg, 150 mg, and 300 mg multi-use vials in a concentration of 6 mg/mL. Store at room temperature. Protect from light. If refrigerated, product may precipitate; precipitate redissolves at room temperature. Non-medicinal ingredients per mL of solution: 527 mg Cremophor® EL (polyethoxylated castor oil) and 46.5%(v/v) alcohol.32,33 For basic information on the current brand used at BC Cancer, see Chemotherapy Preparation and Stability Chart in Appendix.
SOLUTION PREPARATION AND COMPATIBILITY: For basic information on the current brand used at BC Cancer, see Chemotherapy Preparation and Stability Chart in Appendix. Additional information: • concentrated solution must be diluted prior to IV infusion1,7 • to prevent extraction of plasticizer DEHP from container, prepare solutions in non-DEHP containers and
administer using non-DEHP administration sets.1,7 Compatibility: consult detailed reference
PARENTERAL ADMINISTRATION: BC Cancer administration guideline noted in bold, italics
Subcutaneous no information found Intramuscular no information found
BC Cancer administration guideline noted in bold, italics Direct intravenous not recommended; dilution required prior to
administration1,7 Intermittent infusion over 1-3 h5,34-36; use non-DEHP administration sets and
inline filters no greater than 0.22 microns31,33,37 Continuous infusion has been given1,7 Intraperitoneal infuse into abdominal cavity as rapidly as possible
by gravity (use non-DEHP equipment)2,38,39 hyperthermic intraperitoneal chemotherapy (HIPEC):
pump solution into abdominal cavity and circulate as per protocol using hyperthermia pump; solutions and dwell time vary by protocol40,41
Intrapleural no information found Intrathecal no information found Intra-arterial no information found Intravesical no information found
DOSAGE GUIDELINES: Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response, and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.
Adults: BC Cancer usual dose noted in bold, italics Cycle Length: Intravenous: 3 weeks42,43: 80 mg/m2 IV for one dose on days 1, 8 and 15
(total dose per cycle 240 mg/m2) 3 weeks44-60: 175 mg/m2 (range 135-175 mg/m2) IV for one dose on day 1
(total dose per cycle 135-175 mg/m2) 3 weeks61-64: 200 mg/m2 IV for one dose on day 1
(total dose per cycle 200 mg/m2) 4
weeks34,35,42,65- 67
80 mg/m2 IV for one dose on days 1, 8, 15 and 21 (total dose per cycle 320 mg/m2)
4 weeks68: 110 mg/m2 IV for one dose on days 1, 8 and 15
(total dose per cycle 330 mg/m2) Premedication regimen2,7,19,25,26,65,69:
30 minutes before paclitaxel: dexamethasone 20 mg IV PLUS diphenhydramine 50 mg IV PLUS ranitidine 50 mg IV
Paclitaxel
BC Cancer Drug Manual© All rights reserved. Page 8 of 11 Paclitaxel This document may not be reproduced in any form without the express written permission of BC Cancer Provincial Pharmacy. Developed: 1 June 2012 Revised: 30 December 2019
BC Cancer usual dose noted in bold, italics Cycle Length:
alternate regimen: 12 h and 6 h before paclitaxel: dexamethasone 20 mg PO PLUS 30 minutes before paclitaxel: diphenhydramine 50 mg IV PLUS ranitidine 50 mg IV
Concurrent radiation: has been given7 Dosage in myelosuppression: modify according to protocol by which patient is being treated; if no guidelines
available, refer to Appendix "Dosage Modification for Myelosuppression" Dosage in renal failure1,6: no dosage adjustment required for creatinine clearance less than 50 mL/min Dosage in hepatic failure2,6: Suggested guidelines for first course; subsequent courses should be based on
individual tolerance ALT or AST bilirubin dose
<10 X ULN and ≤1.25 X ULN 175 mg/m² <10 X ULN and 1.26-2 X ULN 135 mg/m² <10 X ULN and 2.01-5 X ULN 90 mg/m² ≥10 X ULN or >5 X ULN not recommended
Dosage in dialysis:
hemodialysis: no significant removal2; may give standard dose before or after hemodialysis70-72 chronic ambulatory peritoneal dialysis(CAPD): no significant removal; may give standard dose before or after CAPD71-73
Children: Cycle Length: Intravenous: 3 weeks8,74: 135-250 mg/m² IV for one dose on day 1 3 weeks75,76: 200-350 mg/m² IV for one dose on day 1
REFERENCES: 1. Biolyse. PACLITAXEL FOR INJECTION® product monograph. St. Catherines, Ontario; 2 December 2005. 2. AHFS Drug Information® (database on the Internet). Paclitaxel. Lexi-Comp Inc., November 2011. Available at: http://online.lexi.com. Accessed 7 February 2012. 3. Dizon DS, Schwartz J, Rojan A, et al. Cross-sensitivity between paclitaxel and docetaxel in a women's cancers program. Gynecologic Oncology 2006(100):149-151. 4. Cresteil T, Monsarrat B, Dubois J, et al. Regioselective metabolism of taxoids by human cyp3A4 and 2C8: structure-activity relationship. Drug Metabolism and Disposition 2004;30(4):438-445. 5. Lexi-Drugs® (database on the Internet). Paclitaxel. Lexi-Comp Inc., January 2012. Available at: http://online.lexi.com. Accessed 7 February 2012. 6. Basow DS editor. Paclitaxel. Topic 9735 Version 26.0 ed. Waltham, Massachusetts: UpToDate®; accessed 28 February 2012. 7. Bristol-Myers Squibb Canada. TAXOL® product monograph. Montreal, Ontario; 22 February 2010. 8. Pizzo P, Poplack D. Principles and Practice of Pediatric Oncology. 6th ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2011. p. 292-294, 325. 9. Joerger M, Huitema ADR, Huizing MT, et al. Safety and pharmacology of paclitaxel in patients with impaired liver function: a population pharmacokinetic-pharmacodynamic study. Br J Clin Pharmacol 2007;64(5):622-633. 10. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 8th ed. Philadelphia: Williams & Wilkins; 2008. p. 1389- 1391.
11. Anna Tinker MD. BC Cancer Agency Gynecology Tumour Group. Personal communication. 29 March 2012. 12. Caroline Lohrisch MD. BC Cancer Agency Breast Tumour Group. Personal communication. 05 April 2012. 13. James Conklin Pharmacist. BC Cancer Agency Gynecology Tumour Group. Personal communication. 29 March 2012. 14. Kimberly Kuik. Pharmacist, BC Cancer Agency Breast Tumour Group. Personal communication. 13 April 2012. 15. BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 Mar 2012. 16. Stanford BL, Hardwicke F. A review of clinical experience with paclitaxel extravasations. Support Care Cancer May 2003;11(5):270-277. 17. Anne-Catherine McDuff. Associate Medical Information and Drug Safety, Bristol-Myers Squibb Canada. Personal communication. 18 October 2005. 18. BC Cancer Agency Provincial Systemic Therapy Program. Provincial Systemic Therapy Program Policy III-20: Prevention and Management of Extravasation of Chemotherapy. Vancouver, British Columbia: BC Cancer Agency; 1 August 2014. 19. Kintzel PE. Prophylaxis for paclitaxel hypersensitivity reactions. Ann Pharmacother 2001;35(9):1114-1117. 20. Nguyen VH, Lawrence HJ. Use of gabapentin in the prevention of taxane-induced arthralgias and myalgias. J Clin Oncol 2004;22(9):1767-1769. 21. Garrison JA, McCune JS, Livingston RB, et al. Myalgias and arthralgias associated with paclitaxel. Oncology 2003;17(2):1-11. 22. Turker H, Unsal M, Onar MK. Gabapentin in taxane-induced arthralgia. The Pain Clinic 2006;18(3):271-276. 23. Karen Gelmon MD. Medical Oncolgist, BC Cancer Agency Breast Tumour Group. Personal communication. February 18, 2006. 24. Lee C, Gianos M, Klaustermeyer WB. Diagnosis and management of hypersensitivity reactions related to common cancer chemotherapy agents. Ann Allergy Asthma Immunol 2009(102):179-187. 25. Micha JP, Rettenmaier MA, Dillman R, et al. Single-dose dexamethasone paclitaxel premedication.…
BC Cancer Drug Manual© All rights reserved. Page 1 of 11 Paclitaxel This document may not be reproduced in any form without the express written permission of BC Cancer Provincial Pharmacy. Developed: 1 June 2012 Revised: 30 December 2019
DRUG NAME: Paclitaxel SYNONYM(S): benzenepropanoic acid1 COMMON TRADE NAME(S): TAXOL®, ONXOL® CLASSIFICATION: antimicrotubule agent
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
MECHANISM OF ACTION: Paclitaxel is a taxane. Paclitaxel binds to tubulin, the protein component of microtubules, simultaneously promoting their assembly and disassembly to form stable, nonfunctional microtubules.1,2 Although some reports indicate a cross-reactivity rate of 90% between docetaxel and paclitaxel, others suggest it does not occur consistently.2,3 Stabilization of microtubules blocks cells in the M phase of the cell cycle, inhibiting cell division and causing cell death.2 Paclitaxel acts as a radiosensitizing agent by blocking cells in the G2phase.4 Paclitaxel is an immunosuppressant.5,6
PHARMACOKINETICS: Oral Absorption no information found Distribution biphasic: initial distribution to peripheral compartment, then slow efflux from the peripheral
compartment; widely distributed into body fluids and tissues1,7; small changes in dose may lead to large changes in peak plasma concentrations and total drug exposure due to saturable, nonlinear pharmacokinetics2 cross blood brain barrier?2,8 no volume of distribution1,2,5,6 67 L/m² for 1-6 h infusion; varies with dose and infusion
time; 198-688 L/m² for 24 h infusion plasma protein binding1,2,5 88-98%
Metabolism extensively metabolized in liver via CYP 2C8 (primarily) and CYP 3A4; activity of metabolites is unknown1,2,7 metabolite(s)2,4,9 • 67% as 6α-hydroxypaclitaxel via CYP 2C8;
• 37% as 3-p-hydroxypaclitaxel and 6α,3-p- dihydroxypaclitaxel via CYP 3A4
Excretion primarily via bile1,2,5,7,8 urine 14% (1-13% as unchanged drug) feces 71% (5% as unchanged drug) terminal half life1,2,6,7 10 h; varies with dose and infusion time clearance1,2,7 12 L/h/m²; varies with dose and infusion time
Children2 clearance: 19 to 260 L/m²
Adapted from standard reference7 unless specified otherwise.
Paclitaxel
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USES: Primary uses: Other uses: *Breast cancer Lung cancer, small cell2 *Lung cancer, non-small cell Esophageal cancer2 *Ovarian cancer Bladder cancer2 *Kaposi’s Sarcoma Head and Neck cancer2 Cervical cancer2 Endometrial cancer2
*Health Canada approved indication
SPECIAL PRECAUTIONS: Caution: • preexisting liver impairment may impair elimination of paclitaxel1,7; dose reduction is suggested2,9 Special populations: • elderly patients may have more myelosuppression, neuropathy and cardiovascular toxicities2 • patients with AIDS-related Kaposi’s sarcoma may have more hematologic toxicities, infections and febrile
neutropenia.7 Carcinogenicity: no information found Mutagenicity: Not mutagenic in Ames test and mammalian in vitro mutation test. Paclitaxel is clastogenic in human lymphocytes in vitro but not in other mammalian in vivo chromosome tests.1,2,7 Fertility: In animal studies, reduced fertility has been observed, with decreased pregnancy rates and increased embryo loss in females and testicular atrophy/degeneration in males.1,2 Pregnancy: FDA Pregnancy Category D.5,10 There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). Paclitaxel has shown to be embryotoxic and fetotoxic in animal studies; soft tissue and skeletal malformations have been reported.1,2,7 Breastfeeding is not recommended due to the potential secretion into breast milk.1,2,7
SIDE EFFECTS: The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials.11-14
ORGAN SITE SIDE EFFECT
blood and lymphatic system/ febrile neutropenia
anemia (62-78%, severe 6-16%)1,7
febrile neutropenia (2%)6
leukopenia (86-90%, severe 4-17%)1,7
neutropenia (87-90%, severe 27-52%)1,2,7; nadir 10-12 days, recovery 15-21 days; may require dose reduction
Paclitaxel
BC Cancer Drug Manual© All rights reserved. Page 3 of 11 Paclitaxel This document may not be reproduced in any form without the express written permission of BC Cancer Provincial Pharmacy. Developed: 1 June 2012 Revised: 30 December 2019
ORGAN SITE SIDE EFFECT
Clinically important side effects are in bold, italics
thrombocytopenia (6-20%, severe 1-7%)1,2,7; nadir 8-9 days2
cardiac bradycardia (3-4%); first 3 h of infusion1,7; see paragraph following Side Effects table
cardiovascular events (severe 1-2%)1,7; see paragraph following Side Effects table
ear and labyrinth hearing loss, tinnitus, vertigo, ototoxicity (<1%)
eye optic nerve and/or visual disturbances, photopsia, visual floaters (<1%); generally reversible, may be dose-related
gastrointestinal emetogenic potential: low-moderate15
anorexia (25%)1
constipation (18%)1
nausea and vomiting (44-52%)
general disorders and administration site conditions
extravasation hazard: irritant,16,17 treat as vesicant18; see paragraph following Side Effects table edema (17-21%, severe 1%); localized under skin at no specific site
fever (12%)7
immune system hypersensitivity reactions (5-42%, severe 1-2%)1,7,19; see paragraph following Side Effects table
infections and infestations
infections (18-30%, severe 1%); primarily urinary tract and upper respiratory tract1,7
injury, poisoning, and procedural complications
radiation recall dermatitis2
investigations ECG abnormalities (8-14%, severe <1%)1,2,7; see paragraph following Side Effects table alkaline phosphatase, elevated (18-22%, severe 1%)1,7
AST, elevated (18-19%, severe 1%)1,7
bilirubin, elevated (4-7%, severe 1%)1,7
musculoskeletal and connective tissue
motor neuropathy, with resultant minor distal weakness (<1%)
peripheral neuropathy (52-64% severe 2-4%)1,7; see paragraph following Side Effects table
respiratory, thoracic and mediastinal
Paclitaxel
BC Cancer Drug Manual© All rights reserved. Page 4 of 11 Paclitaxel This document may not be reproduced in any form without the express written permission of BC Cancer Provincial Pharmacy. Developed: 1 June 2012 Revised: 30 December 2019
ORGAN SITE SIDE EFFECT
skin and subcutaneous tissue
alopecia (87-93%)1,7; usually complete, generally occurs 14-21 days after administration of paclitaxel; onset sudden, often occurring in a single day2 nail discolouration (2%)7
rash (12-14%)1,7
phlebitis1,7
Adapted from standard reference7 unless specified otherwise.
Arthralgia/myalgia may be severe in some patients; however, there is no consistent correlation between cumulative dose and infusion duration of paclitaxel and frequency or severity of the arthralgia/myalgia. Symptoms are usually transient, occurring within 2 or 3 days after paclitaxel administration, and resolving within days.2,7 If arthralgia/myalgia is not relieved by adequate doses of ibuprofen, or short-term, low-dose dexamethasone or prednisone20,21, gabapentin may be tried.20-22 Dose reducing paclitaxel may lessen the severity of arthralgias/myalgias; however, there is no data on efficacy of reduced doses in a curative setting. Dose reduction should be considered only if symptom severity precludes continuing paclitaxel.11,12,23 Cardiovascular effects present as bradycardia, hypotension and ECG changes. Bradycardia and hypotension typically occur during the first 3 hours of infusion; however, they are usually asymptomatic and do not require treatment. Paclitaxel administration may require interruption or discontinuation in some cases. Frequency of hypotension and bradycardia is not influenced by dose, schedule or prior anthracycline therapy. Common ECG changes are non-specific repolarization abnormalities, sinus bradycardia, sinus tachycardia, and premature beats. Among patients with normal ECG at baseline, prior therapy with anthracyclines did not influence the frequency of ECG abnormalities. Severe cardiovascular effects are rarely reported, including cases of atrial fibrillation, supraventricular tachycardia, myocardial infarction, congestive heart failure, and thromboembolic events. When reported, these patients had underlying disease or previous radiotherapy or chemotherapy which was thought to have contributed to the event.2,7 Paclitaxel extravasation may rarely cause local tissue necrosis, leading to the suggestion that paclitaxel may have vesicant properties. In some reports, patients have experienced recall reactions from previous paclitaxel extravasations. No correlation has been made between concentration or volume of paclitaxel extravasated and the risk of tissue necrosis. Extravasation injuries due to paclitaxel may be either immediate or delayed and thus patients may require an extended follow-up; patient complaints of pain, burning, or stinging at the injection site occurring several days after the infusion should be investigated. Specific treatment recommendations for paclitaxel extravasation are still unclear as experience is anecdotal.7,16,17 For management of extravasation reactions, see BC Cancer Policy Number III-20 Prevention and Management of Extravasation of Chemotherapy. Hypersensitivity reactions typically occur within the first 10 minutes of the first two cycles.2,24 Reactions are caused by either a histamine release in response to polyoxyl 35 castor oil (Cremophor® EL), or a non-IgE mediated reaction to the taxane moiety. Frequent, minor hypersensitivity reactions include: flushing (28%), rash (12%), hypotension (4%), dyspnea (2%), tachycardia (2%), and hypertension (1%). Chills, abdominal pain, and back pain are more rare.2,7 Severe hypersensitivity reactions include: dyspnea requiring bronchodilators, hypotension requiring treatment, flushing, chest pain, tachycardia, angioedema, and generalized urticaria. Severe reactions rarely occur after the third cycle of treatment.2,7 The incidence and severity of hypersensitivity reactions are reduced with premedication although rare, fatal reactions may occur despite premedication.7. A single IV dexamethasone dose with an antihistamine and an H2-antagonist reduces the incidence of hypersensitivity reactions from 40% to 2-3%.7,25 The frequency and severity of hypersensitivity reactions are not affected by the dose or duration of infusion of paclitaxel.7,26 For management of hypersensitivity reactions, see BC Cancer Protocol SCDRUGRX Management of Hypersensitivity Reactions to Chemotherapeutic Agents.
Rechallenge after a severe hypersensitivity reaction: The occurrence of hypersensitivity reactions does not preclude rechallenge with paclitaxel. In the event of a hypersensitivity reaction, the patient may be rechallenged the same day after additional premedication, slowing the rate of infusion, and close monitoring.23,25 Subsequent cycles may benefit from a regimen of oral dexamethasone given 12 and 6 hours before paclitaxel, plus antihistamines and H2-antagonists given 30 minutes to 1 hour before paclitaxel.24,26,27 Consider substituting paclitaxel with docetaxel or implementing a desensitization protocol if a patient develops a reaction following a rechallenge.24 For management of hypersensitivity reactions, see BC Cancer Protocol SCDRUGRX Management of Hypersensitivity Reactions to Chemotherapeutic Agents. Peripheral sensory neuropathy presents with numbness and tingling in a stocking-and-glove distribution, perioral numbness, and hyperesthesia. Onset of symptoms can be within days following infusion. Frequency of symptoms increases with repeated exposure and cumulative dose.2,7 Pre-existing neuropathies from prior therapies are not a contraindication for treatment with paclitaxel; however, the incidence of neuropathy appears to be increased in this patient population. A dose reduction of 20% is recommended for all subsequent cycles of paclitaxel for patients who experience severe peripheral neuropathy. Sensory neuropathy usually improves or resolves within months of paclitaxel discontinuation.7
INTERACTIONS:
paclitaxel clearance is decreased by 25-33% when given after cisplatin
preferred method is to give paclitaxel first when administering as sequential infusions
dexamethasone1,7 does not affect protein binding of paclitaxel
diphenhydramine1 does not affect protein binding of paclitaxel
disulfiram29 development of acute alcohol intolerance reactions
inhibition of aldehyde dehydrogenase by disulfiram, leading to development of toxic metabolites of ethanol (found in the solution)
avoid disulfiram concurrently with paclitaxel administration
doxorubicin2,7,28 may increase cardiac toxicity from doxorubicin when given concurrently with paclitaxel
doxorubicin clearance is decreased leading to increased plasma levels of doxorubicin and doxorubicinol
monitor for increased cardiotoxicity
metronidazole and derivatives29
development of acute alcohol intolerance reactions; the risk for most patients appears slight
inhibition of aldehyde dehydrogenase by metronidazole, leading to development of toxic metabolites of ethanol (found in solution)
avoid metronidazole and its derivatives concurrently with paclitaxel administration
vaccines, live29 enhanced viral replication may increase the risk of disseminated disease
decreased immune response allows live vaccine to produce infection
avoid live vaccines during treatment
BC Cancer Drug Manual© All rights reserved. Page 6 of 11 Paclitaxel This document may not be reproduced in any form without the express written permission of BC Cancer Provincial Pharmacy. Developed: 1 June 2012 Revised: 30 December 2019
AGENT EFFECT MECHANISM MANAGEMENT
warfarin29 may increase anticoagulant effect of warfarin when given concurrently with paclitaxel
paclitaxel may displace warfarin from plasma protein binding sites when given concurrently
monitor INR and adjust warfarin dosing accordingly; consider use of LMWH with chemotherapy30
Paclitaxel is a substrate of CYP 3A4 and CYP 2C8 isoenzymes. Strong inhibitors of CYP 3A4 or 2C8 may decrease paclitaxel metabolism resulting in increased plasma levels and toxicity. Avoid concurrent use if possible; if unavoidable, consider reducing the paclitaxel dose.2,7,28 Strong inducers of CYP 3A4 or 2C8 may increase paclitaxel metabolism, potentially resulting in a reduced therapeutic effect of paclitaxel.1,2,7
SUPPLY AND STORAGE: Injection: Accord Healthcare Inc. supplies paclitaxel as 30 mg, 100 mg, and 300 mg vials in a concentration of 6 mg/mL. Store at room temperature. Product may precipitate if refrigerated; precipitate redissolves at room temperature. Non- medicinal ingredients per mL of solution: 527 mg Cremophor® EL (polyethoxylated castor oil) and 39.1%(w/v) ethanol.31 Biolyse Pharma supplies paclitaxel as 30 mg and 100 mg single dose vials and a 300 mg multi-dose vial in a concentration of 6 mg/mL. Refrigerate. Do not freeze. Potency is not affected when transported or stored for up to 2 months at room temperature. Non-medicinal ingredients per mL of solution: 527 mg Cremophor® EL (polyethoxylated castor oil) and 49.7%(v/v) alcohol.1 Pfizer Canada Inc. (Hospira Healthcare) supplies paclitaxel as 30 mg, 100 mg, 150 mg, and 300 mg multi-use vials in a concentration of 6 mg/mL. Store at room temperature. Protect from light. If refrigerated, product may precipitate; precipitate redissolves at room temperature. Non-medicinal ingredients per mL of solution: 527 mg Cremophor® EL (polyethoxylated castor oil) and 46.5%(v/v) alcohol.32,33 For basic information on the current brand used at BC Cancer, see Chemotherapy Preparation and Stability Chart in Appendix.
SOLUTION PREPARATION AND COMPATIBILITY: For basic information on the current brand used at BC Cancer, see Chemotherapy Preparation and Stability Chart in Appendix. Additional information: • concentrated solution must be diluted prior to IV infusion1,7 • to prevent extraction of plasticizer DEHP from container, prepare solutions in non-DEHP containers and
administer using non-DEHP administration sets.1,7 Compatibility: consult detailed reference
PARENTERAL ADMINISTRATION: BC Cancer administration guideline noted in bold, italics
Subcutaneous no information found Intramuscular no information found
BC Cancer administration guideline noted in bold, italics Direct intravenous not recommended; dilution required prior to
administration1,7 Intermittent infusion over 1-3 h5,34-36; use non-DEHP administration sets and
inline filters no greater than 0.22 microns31,33,37 Continuous infusion has been given1,7 Intraperitoneal infuse into abdominal cavity as rapidly as possible
by gravity (use non-DEHP equipment)2,38,39 hyperthermic intraperitoneal chemotherapy (HIPEC):
pump solution into abdominal cavity and circulate as per protocol using hyperthermia pump; solutions and dwell time vary by protocol40,41
Intrapleural no information found Intrathecal no information found Intra-arterial no information found Intravesical no information found
DOSAGE GUIDELINES: Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response, and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.
Adults: BC Cancer usual dose noted in bold, italics Cycle Length: Intravenous: 3 weeks42,43: 80 mg/m2 IV for one dose on days 1, 8 and 15
(total dose per cycle 240 mg/m2) 3 weeks44-60: 175 mg/m2 (range 135-175 mg/m2) IV for one dose on day 1
(total dose per cycle 135-175 mg/m2) 3 weeks61-64: 200 mg/m2 IV for one dose on day 1
(total dose per cycle 200 mg/m2) 4
weeks34,35,42,65- 67
80 mg/m2 IV for one dose on days 1, 8, 15 and 21 (total dose per cycle 320 mg/m2)
4 weeks68: 110 mg/m2 IV for one dose on days 1, 8 and 15
(total dose per cycle 330 mg/m2) Premedication regimen2,7,19,25,26,65,69:
30 minutes before paclitaxel: dexamethasone 20 mg IV PLUS diphenhydramine 50 mg IV PLUS ranitidine 50 mg IV
Paclitaxel
BC Cancer Drug Manual© All rights reserved. Page 8 of 11 Paclitaxel This document may not be reproduced in any form without the express written permission of BC Cancer Provincial Pharmacy. Developed: 1 June 2012 Revised: 30 December 2019
BC Cancer usual dose noted in bold, italics Cycle Length:
alternate regimen: 12 h and 6 h before paclitaxel: dexamethasone 20 mg PO PLUS 30 minutes before paclitaxel: diphenhydramine 50 mg IV PLUS ranitidine 50 mg IV
Concurrent radiation: has been given7 Dosage in myelosuppression: modify according to protocol by which patient is being treated; if no guidelines
available, refer to Appendix "Dosage Modification for Myelosuppression" Dosage in renal failure1,6: no dosage adjustment required for creatinine clearance less than 50 mL/min Dosage in hepatic failure2,6: Suggested guidelines for first course; subsequent courses should be based on
individual tolerance ALT or AST bilirubin dose
<10 X ULN and ≤1.25 X ULN 175 mg/m² <10 X ULN and 1.26-2 X ULN 135 mg/m² <10 X ULN and 2.01-5 X ULN 90 mg/m² ≥10 X ULN or >5 X ULN not recommended
Dosage in dialysis:
hemodialysis: no significant removal2; may give standard dose before or after hemodialysis70-72 chronic ambulatory peritoneal dialysis(CAPD): no significant removal; may give standard dose before or after CAPD71-73
Children: Cycle Length: Intravenous: 3 weeks8,74: 135-250 mg/m² IV for one dose on day 1 3 weeks75,76: 200-350 mg/m² IV for one dose on day 1
REFERENCES: 1. Biolyse. PACLITAXEL FOR INJECTION® product monograph. St. Catherines, Ontario; 2 December 2005. 2. AHFS Drug Information® (database on the Internet). Paclitaxel. Lexi-Comp Inc., November 2011. Available at: http://online.lexi.com. Accessed 7 February 2012. 3. Dizon DS, Schwartz J, Rojan A, et al. Cross-sensitivity between paclitaxel and docetaxel in a women's cancers program. Gynecologic Oncology 2006(100):149-151. 4. Cresteil T, Monsarrat B, Dubois J, et al. Regioselective metabolism of taxoids by human cyp3A4 and 2C8: structure-activity relationship. Drug Metabolism and Disposition 2004;30(4):438-445. 5. Lexi-Drugs® (database on the Internet). Paclitaxel. Lexi-Comp Inc., January 2012. Available at: http://online.lexi.com. Accessed 7 February 2012. 6. Basow DS editor. Paclitaxel. Topic 9735 Version 26.0 ed. Waltham, Massachusetts: UpToDate®; accessed 28 February 2012. 7. Bristol-Myers Squibb Canada. TAXOL® product monograph. Montreal, Ontario; 22 February 2010. 8. Pizzo P, Poplack D. Principles and Practice of Pediatric Oncology. 6th ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2011. p. 292-294, 325. 9. Joerger M, Huitema ADR, Huizing MT, et al. Safety and pharmacology of paclitaxel in patients with impaired liver function: a population pharmacokinetic-pharmacodynamic study. Br J Clin Pharmacol 2007;64(5):622-633. 10. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 8th ed. Philadelphia: Williams & Wilkins; 2008. p. 1389- 1391.
11. Anna Tinker MD. BC Cancer Agency Gynecology Tumour Group. Personal communication. 29 March 2012. 12. Caroline Lohrisch MD. BC Cancer Agency Breast Tumour Group. Personal communication. 05 April 2012. 13. James Conklin Pharmacist. BC Cancer Agency Gynecology Tumour Group. Personal communication. 29 March 2012. 14. Kimberly Kuik. Pharmacist, BC Cancer Agency Breast Tumour Group. Personal communication. 13 April 2012. 15. BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 Mar 2012. 16. Stanford BL, Hardwicke F. A review of clinical experience with paclitaxel extravasations. Support Care Cancer May 2003;11(5):270-277. 17. Anne-Catherine McDuff. Associate Medical Information and Drug Safety, Bristol-Myers Squibb Canada. Personal communication. 18 October 2005. 18. BC Cancer Agency Provincial Systemic Therapy Program. Provincial Systemic Therapy Program Policy III-20: Prevention and Management of Extravasation of Chemotherapy. Vancouver, British Columbia: BC Cancer Agency; 1 August 2014. 19. Kintzel PE. Prophylaxis for paclitaxel hypersensitivity reactions. Ann Pharmacother 2001;35(9):1114-1117. 20. Nguyen VH, Lawrence HJ. Use of gabapentin in the prevention of taxane-induced arthralgias and myalgias. J Clin Oncol 2004;22(9):1767-1769. 21. Garrison JA, McCune JS, Livingston RB, et al. Myalgias and arthralgias associated with paclitaxel. Oncology 2003;17(2):1-11. 22. Turker H, Unsal M, Onar MK. Gabapentin in taxane-induced arthralgia. The Pain Clinic 2006;18(3):271-276. 23. Karen Gelmon MD. Medical Oncolgist, BC Cancer Agency Breast Tumour Group. Personal communication. February 18, 2006. 24. Lee C, Gianos M, Klaustermeyer WB. Diagnosis and management of hypersensitivity reactions related to common cancer chemotherapy agents. Ann Allergy Asthma Immunol 2009(102):179-187. 25. Micha JP, Rettenmaier MA, Dillman R, et al. Single-dose dexamethasone paclitaxel premedication.…
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